Shafali Spurling Jeste, MD Associate Professor in Psychiatry, Neurology and Pediatrics UCLA David Geffen School of Medicine Director, CARING Clinic UCLA Center for Autism Research and Treatment Clinical trial readiness for syndromic neurodevelopmental disorders Tarjan Lecture Series April 20, 2020
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Shafali Spurling Jeste, MDAssociate Professor in Psychiatry, Neurology and Pediatrics
UCLA David Geffen School of Medicine
Director, CARING Clinic
UCLA Center for Autism Research and Treatment
Clinical trial readiness for syndromic neurodevelopmental disorders
Tarjan Lecture SeriesApril 20, 2020
Funding sources: NIH, Autism Speaks, Dup15q alliance, DoD
Consultant for Roche Pharmaceuticals and Yamo Pharmaceuticals
Editor-in-Chief of AAN Continuum Child Neurology Edition
Speakers Bureau for Medical Education Network
Financial Disclosures
Talk outline
• Overview of syndromic neurodevelopmental disorders
• Clinical trial readiness – concepts and data
• Next steps
Karyotyping and FISH (Florescent in situ Hybridization)3-5 million BPs
Chromosomal Microarray100 Kb
Whole exome and genome sequencingAnalysis at the level of single base pair
Advances in methods to examine ASD genetics
Ramaswami, 2018
Schaefer et al, 2013
Genetic testing is the only routinely recommended medical workup for individuals with ASD
Family meetingsOrlando 2015Redondo Beach 2017Houston 2019
62 children ages 2.5-18
Developmental domains to assess
• Cognition
• Motor skills
• Adaptive skills
• Social skills
Distefano et al, JNDD 2016
Bishop et al, 2016, 2017
0
50
100
Domain
Sta
nd
ard
Sco
re
Cognitive Ability - Idic
No Epilepsy
Epilespy
Verba
l
Non
-Ver
bal
0 5 10 15 20 25 30 35 40 45 50 55 60 65
0
2
4
6
8
Histogram of NVIQ
NVIQ
Nu
mb
er
of
valu
es
0
50
100
Domain
Sta
nd
ard
Sco
re
Adaptive Behavior - Idic
Com
mun
icat
ion
Daily L
iving
Skills
Socializ
ation
Mot
or
No Epilepsy
Epilespy
20 25 30 35 40 45 50 55 60 65 70 75 80
0
2
4
6
8
Histogram of Adaptive Behavior Composite
Adaptive Behavior Composite
Nu
mb
er
of
valu
es
Distefano et al, American Journal of Medical Genetics, 2020
• Social Responsiveness Scale (Constantino, 2003)
“Gives unusual or illogical reasons for doing things”“Is aware of what others are thinking or feeling”
• Child Behavior Checklist (Achenbach, 2001)
• “Can’t get his/her mind of certain thoughts”• “Feels or complains that no one loves him/her”
Distefano et al, American Journal of Medical Genetics, 2020
Standardized questionnaires are problematic in severe ID
Wilson et al, Autism Research 2020
• Determine the most meaningful and measurable clinical endpoints
Adaptive skills interview provides more stratification
Ratio IQ scores may prevent clustering at the “floor”
Need to measure motor skills – quantitative tools can be used
Individuals with epilepsy overall have more developmental challenges
Goals for clinical trial readiness...
• Determine the most meaningful and measurable clinical endpoints
• Identify mechanistic biomarkers that can inform drug target engagement (and perhaps patient selection)
• Design protocols and develop methods that maximize access and scalability
“Characteristic that is objectively measured and evaluated as an indication of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions”
Robb and McInnes, JAMA, 2016; FDA-NIH Biomarker Working Group, 2016
Urraca et al, 2018
Dup15q syndrome
• Initial acclimation
• explore room, favorite movie playing, reinforcers, rapport building
• Netting
• training net, modeled by parent, incremental practice with reinforcers, favorite move playing
• Recording
• experimenter with child, verbal/physical reminders, pause for reinforcers as needed
Frohlich et al, PLoS One, 2016
Log
po
wer
Dup15q TDnsASD
p = 6 10-4, FDR p = 6 10-4, FDR
Frequency (Hz)Frohlich et al, Molecular Autism 2018; Saravanpandian et al, under revisions 2020
PROPERTY RESULTS
Stable over time? YES
Scalable? YES
Relate to phenotype? YES (epilepsy)
Change with state? YES (SLEEP!!)
Frohlich et al, Mol Autism 2019
Genetic Etiology
Effects on neural
functionBiomarker
Clinical symptoms
TargetedTreatment Outcome
Hypotonia/global delay, autism, epilepsy
motor,
adaptive skills
sleep
precision health...
Goals for clinical trial readiness...
• Determine the most meaningful and measurable clinical endpoints
• Identify mechanistic biomarkers that can inform drug target engagement (and perhaps patient selection)
• Design protocols and develop methods that maximize access and scalability
Tuberous Sclerosis Complex (TSC)
Loss of function mutation in TSC1/TSC2 genes
ASD in >50% (Jeste et al, 2007, 2009)
Early diagnosis: often in utero (Datta 2008; Davis, 2017)
Kasari et al, 2015; Chang et al, 2016; Shire et al, 2017, 2019ClinicalTrials.gov Identifier: NCT03422367
Hyde et al, Journal of Neurodevelopmental Disorders, 2020
“I wanted to let you know that we have decided to not do the trial. My husband won’t be able to receive the time off to be able to travel with me. We are extremely disappointed and hope that maybe another trial comes up at a later time for my little ones.”
“Thank you for the information! We would love to participate, but unfortunately due to the travel we won’t be able to. We are already traveling 1-2 times per month for his appointments. If virtual ever becomes an option we’d be interested.”
Hyde et al, Journal of Neurodevelopmental Disorders, 2020
Hyde et al, Journal of Neurodevelopmental Disorders, 2020
• Design protocols and develop methods that maximize access and scalability
Listen to and partner with families
Continue to innovate to develop effective and feasible remote assessment and delivery strategies
“Perfect is the enemy of the good”
Remote Assessment in Dup15q Syndrome
BOSCC BOSCC BOSCC
1 week 6 months
Test-retestNatural change
Construct Activity Measures
Visual attention 3-min video on tablet Behavioral looking, heart-defined
attention
Temperament Arm restraint during
play
Behavioral response, physiological
arousal
Language
Social
Motor
Play
Unstructured play Behavioral coding, LENA analysis, dyadic
patterns (LENA and heart rate), BOSCC
coding Parent-child interaction
Ovid TAK-935-18-002: Open label, phase 1 pilot study of TAK-935 (OV935) in individuals with 15Q Duplication Syndrome or CDKL5 Deficiency Disorder (ARCADE)
Ovid TAK-935-18-001: Phase 2, prospective, open-label extension study to assess the long-term safety and tolerability of TAK-935 (OV935) as adjunctive therapy in patients with rare epilepsy (Endymion)
Ages 2-18
Roche BP41674: Open-label, phase 1 clinical trial of RO7248824 (ASO) in individuals with Angelman Syndrome (AS)
Ages 1-12
GeneTx GTX-102-001: Phase 1/2 open-label, dose-escalating clinical trial of GTX-102 (ASO) in individuals with Angelman syndrome (AS)